- Crime fiction, Polish Literature, Dialects of English, Czech Literature, Popular Fiction, Jewish heritage, Polish-Jewish / German-Jewish Relations, klezmer revival, Jewish heritage tourism, Holocaust commemoration, antisemitism, social identity, oral history, and 4 morePolish History, National Identity, Post-Colonialism, and Ukrainian Studiesedit
GM-CSF has been used in clinical trials to assess its role in promoting the proliferation and differentiation of marrow cells and enhancing the functional activities of granulocytes and monocytes. These studies have indicated that GM-CSF... more
GM-CSF has been used in clinical trials to assess its role in promoting the proliferation and differentiation of marrow cells and enhancing the functional activities of granulocytes and monocytes. These studies have indicated that GM-CSF may prove useful in the management of cancer patients by preventing or treating myelosuppression following cancer chemotherapy and in patients with myelodysplasia or aplastic anaemia. As well as determining the efficacy of GM-CSF as a therapeutic agent, these studies are also providing insights into the possible roles of GM-CSF in vivo. Pharmacokinetic studies of GM-CSF in patients with advanced cancer and myelodysplasia suggest that the ratio of efficacy to toxicity of GM-CSF can be modified by changing either the dose or the method of administration.
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Chromosomal analysis of human hemopoietic malignancies has resulted in a better understanding of their etiology, improved their classification, allowed a better prediction of prognosis, and proved useful for the detection of malignant... more
Chromosomal analysis of human hemopoietic malignancies has resulted in a better understanding of their etiology, improved their classification, allowed a better prediction of prognosis, and proved useful for the detection of malignant cells present in low frequency in the bone marrow samples. An example of the usefulness of chromosomal analysis in the myeloid leukemias is the identification of the Philadelphia chromosome in Chronic Granulocytic Leukemia and of a new protein encoded by the abl bcr genes as a consequence of the translocation of the abl proto-oncogene to chromosome 22 adjacent to the bcr gene [1]. It is not difficult to extrapolate that these observations will lead to an understanding of the basis for the initiation and maintenance of the malignancy. Other examples in which specific nonran-dom chromosomal abnormalities have been identified include t(15;17) in acute promyelocytic leukemia and the inversion of chromosome 16 in the M4Eo subtype of ANLL [1].
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The production of blood cells is known to be under the control of up to 20 different cytokines [1]. In recent years many of the cytokines have been identified and cloned, and are now in clinical trials. Several of the cytokines, including... more
The production of blood cells is known to be under the control of up to 20 different cytokines [1]. In recent years many of the cytokines have been identified and cloned, and are now in clinical trials. Several of the cytokines, including interleukin-6 (IL-6), interleukin-3 (IL-3) and granulocyte—macrophage colony-stimulating factor (GM-CSF) act upon early progenitor cells, while others, such as granulocyte colony-stimulating factor (G-CSF), macrophage CSF (M-CSF) and erythropoietin, act upon the more mature precursor cells and produce relatively pure populations of granulocytes, monocytes and red blood cells respectively. It is now clear that these cytokines, although acting on a limited number of specific lineages, have very different properties in vivo and in vitro.
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Bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur... more
Bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur during short courses of administration. We have recognized a syndrome of hypoxia and hypotension that follows the first but not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study developed a reaction that occurred after the first dose of 24 of 78 cycles of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24), tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of 24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24), involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did not occur after any of more than 600 second and subsequent consecutive rhGM-CSF doses. Oxygen saturation decreased during first-dose reactions by 8% +/- 4% as compared with 3% +/- 1% on first days without reactions (P less than .001) and 2% +/- 1% on subsequent days (P less than .001). Pulmonary dysfunction was characterized by hypoxemia (59 +/- 9 mm Hg, mean +/- SD) that was fully correctable with supplementary oxygen, decreased single-breath carbon monoxide diffusion capacity, and increased alveolar-arterial oxygen gradients (25 +/- 6 to 60 +/- 4 mm Hg, mean +/- SD), but no significant abnormalities on chest roentgenogram or lung perfusion scan. Factors predisposing to reactions were rhGM-CSF dose greater than or equal to 3 micrograms/kg (P less than .01), intravenous (IV) rather than subcutaneous (SC) administration (P less than .05), occurrence of a reaction after the first dose of a previous cycle of rhGM-CSF therapy (P less than .01), and for patients receiving 15 micrograms/kg/d by SC bolus, the presence of lung cancer (P less than .05). Administration of 15 micrograms/kg/d rhGM-CSF by 24-hour SC infusion rather than SC bolus resulted in a delayed onset of reaction from 30 +/- 8 minutes to 240 +/- 190 minutes (mean +/- SD, P less than .001), and a slower rate of initial transient decrease in neutrophil levels and a more prolonged duration of transient leukopenia. The time of onset of reactions correlated with the rate of rise of rhGM-CSF levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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Native human granulocyte-macrophage colony stimulating factor (hGM-CSF) has previously been purified using methods which typically required several sequential chromatographic steps and only yielded small amounts of hGM-CSF. We have... more
Native human granulocyte-macrophage colony stimulating factor (hGM-CSF) has previously been purified using methods which typically required several sequential chromatographic steps and only yielded small amounts of hGM-CSF. We have purified and characterized hGM-CSF using monoclonal antibodies raised against bacterially synthesized hGM-CSF. Activated donor T-lymphocytes grown in interleukin-2 and then reactivated with phytohemagglutinin produce several forms of hGM-CSF which can be purified using immunoaffinity absorption followed by reversed phase high performance liquid chromatography. The purified hGM-CSF consisted of at least nine species ranging in molecular weight (Mr) from 14,500 to 32,000. The higher Mr forms contained one or two N-linked carbohydrate moieties and were more acidic by two-dimensional Western blot analysis, consistent with increasing sialation. N-terminal sequence analysis of high and low molecular weight hGM-CSF fractions corresponded to that predicted by the cDNA sequence. Using the AML 193 [3H]thymidine incorporation assay the specific activity of the heavily glycosylated hGM-CSF was 1 x 10(8) units/mg compared with 6 x 10(8) units/mg for the non-glycosylated hGM-CSF produced by Escherichia coli. The different hGM-CSF forms induced neutrophil superoxide anion production by a variable amount depending on the extent of N-linked glycosylation. Receptor binding studies demonstrated lower receptor affinity for the heavily glycosylated form (KD = 820 pM) compared to less heavily glycosylated (KD = 78 pM) and non-glycosylated hGM-CSF produced by E. coli (KD = 30 pM). These differences are due to differences in the kinetic association rate.
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Research Interests: Chemotherapy, Adolescent, Hematopoietic Stem Cells, Humans, Female, and 15 moreMale, Bone marrow, Haematopoiesis, Lancet, Clinical Sciences, Bone Marrow Transplantation, Adult, Cyclophosphamide, Antineoplastic Agents, Filgrastim, Hematopoietic Stem Cell Transplantation, Combined Modality Therapy, Cell count, Blood platelets, and leukocyte Count
Summary.During a study of recombinant human granulocyte colony stimulating factor (rhG‐CSF) administration, 15 patients received twice daily i.v. infusions and nine patients received daily s.c. infusions of rhG‐CSF for 5 d prior to... more
Summary.During a study of recombinant human granulocyte colony stimulating factor (rhG‐CSF) administration, 15 patients received twice daily i.v. infusions and nine patients received daily s.c. infusions of rhG‐CSF for 5 d prior to cytotoxic therapy, and then a second course subsequent to melphalan administration. There was a striking dose‐related neutrophilia and the appearance in the blood of early myeloid cells that express the intercellular adhesion molecule CD54. In addition, giant neutrophils or macropolycytes were observed in the peripheral blood of all patients. These cells were evident on the display of the Technicon H*1 as a population of large peroxidase positive cells, and using Feulgen staining these cells were shown to be tetraploid. Bone marrow kinetics studies performed on Day 4 or 5 indicated an increase in the proportion of bone marrow cells in S phase, G2 and mitosis, reflecting a proliferative response of the marrow. Large myeloid precursors and occasional binucl...
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To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Single arm nonrandomized dose escalation study.... more
To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Single arm nonrandomized dose escalation study. Twenty-one patients with advanced malignancy who were not receiving concurrent myelosuppressive therapy. Subcutaneous administration of rhGM-CSF by once-daily injection to groups of two to four patients at doses of 0.3 to 30 micrograms/kg body weight.d for 10 consecutive days. Some patients received a second 10-day period of daily rhGM-CSF treatment after a 10-day nontreatment interval followed by alternate-day treatment. Clinical status and hematologic values were monitored frequently. All doses of rhGM-CSF caused an immediate transient fall of 84% to 99% in circulating neutrophils, eosinophils, and monocytes. Continued daily dosing caused a leukocytosis of up to 10-fold with increases in numbers of circulating neutrophils, eosinophils, monocytes, and lymphocytes. There appeared to be a plateau in the increase in neutrophils in the dose range 3 to 15 micrograms/kg.d. Marrow aspirates showed increased proportions of promyelocytes and myelocytes. Alternate-day injection of 15 micrograms/kg maintained a leukocytosis. At doses up to 15 micrograms/kg.d, rhGM-CSF was well tolerated but adverse effects included bone pains, myalgias, rashes, and liver dysfunction. At doses exceeding 15 micrograms/kg.d, pericarditis was a dose-limiting toxicity. Idiopathic thrombocytopenic purpura was reactivated by rhGM-CSF in one patient. Bacterially synthesized rhGM-CSF induces a leukocytosis in the dose range of 3 to 15 micrograms/kg.d. These doses are appropriate for phase II studies.
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We have undertaken a phase 1 — phase 2 study of the effectiveness of photoirradiation therapy or photodynamic therapy (PDT) in the treatment of advanced esophageal cancer.
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To investigate the degree and type of delays in performing diagnostic biopsies in medical patients with suspected malignancy. Retrospective survey of clinical histories of patients referred between January 1985 and March 1989. Inner city... more
To investigate the degree and type of delays in performing diagnostic biopsies in medical patients with suspected malignancy. Retrospective survey of clinical histories of patients referred between January 1985 and March 1989. Inner city teaching hospital internal medicine (non-oncologic) services. Patients with gastrointestinal and lung cancers, adenocarcinoma of unknown primary site, and lymphomas were referred as inpatients by internists. Two hundred fifty-five patients were eligible, and 177 were evaluable. The number, type, and results of tests done before and after biopsy were analyzed. In 67% of patients the biopsied lesion was detected by the second day of evaluation; however, there was an 8- to 10-day delay before a biopsy was done. This delay was consistent across the four malignancy groups studied. Although logistic and other unavoidable delays occurred in 40% of the cases, in 60% delays could only be attributed to continued, frequently low yield, noninvasive tests. An average of 3.3 tests were made per patient, with only 24% leading to a definitive biopsy. Because of the performance of many other tests, a substantial delay exists in proceeding to biopsy during the diagnosis of cancer by internists.
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A monoclonal antibody, Leo Mel 3, raised against a melanoma cell line (LiBr), binds to a carbohydrate determinant of cell surface gangliosides, the simplest of which is GD3. This monoclonal antibody was screened for by its capacity to... more
A monoclonal antibody, Leo Mel 3, raised against a melanoma cell line (LiBr), binds to a carbohydrate determinant of cell surface gangliosides, the simplest of which is GD3. This monoclonal antibody was screened for by its capacity to block the recognition and lysis of the melanoma cells by cytotoxic T-lymphocytes with anomalous killer cell function, illustrating a novel approach for identifying monoclonal antibody to biologically relevant tumor-associated antigens. Leo Mel 3 reacted selectively with melanoma cells by indirect immunofluorescent and immunoperoxidase staining; it reacted with tissue from all primary and metastatic melanoma tested, and it bound to cells from all but one of six cultured melanoma cell lines. Leo Mel 3 did not react with a variety of carcinomas, lymphomas, leukemias, and other neuroectodermal tumors, nor with adult or fetal tissues, except fetal liver. Very weak staining of cutaneous basal melanocytes was noted in a minority of skin sections, and 50 to 80...
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Six patients with Philadelphia positive chronic myeloid leukaemia (CML) were treated with single high doses of busulphan. The action of busulphan on the in vivo kinetics of circulating progenitor cells (colony forming cells) was measured... more
Six patients with Philadelphia positive chronic myeloid leukaemia (CML) were treated with single high doses of busulphan. The action of busulphan on the in vivo kinetics of circulating progenitor cells (colony forming cells) was measured using an agar culture system which involved scoring of total colonies and clusters at 7 days and of granulocyte, monocyte and eosinophil colonies at 14 days. High dose busulphan was found to be effective in suppressing circulating granulocyte, monocyte and eosinophil progenitor cells. The effect of busulphan on progenitor cells was rapid and their levels fell by at least 85% within five days. By contrast, the white blood cells fell by only 9% and the platelets fell by 10% over this time. Subsequently, the white cell count and platelet count fell to near normal levels. The progenitor cell levels began to rise again at a mean of 35 days following busulphan treatment and the white blood cells at a mean of 39 days in four patients. One patient remained ...
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Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mortality in cancer patients. Empiric antibiotic therapy commencing at the onset of fever is selected according to three principles:... more
Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mortality in cancer patients. Empiric antibiotic therapy commencing at the onset of fever is selected according to three principles: intravenous therapy is used to rapidly achieve bactericidal serum levels, antibiotics with appropriate antibacterial spectra are required, and combinations of antibiotics have been preferred for their synergistic activity. Initial empiric monotherapy with single antibiotics such as imipenem which have a sufficiently broad antibacterial spectrum in their own right are potentially as efficacious as conventional combination therapies. Granulocytopenic periods complicated by fever are significantly longer in patients receiving chemotherapy for leukaemia than in patients undergoing treatment for lymphoma and solid tumours. However, defervescence of fever following commencement of antibiotic therapy occurs equally rapidly in these three groups. The persistent granu...
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More than 20% of human granulocyte-macrophage and eosinophil colony-forming cells survived in agar culture for up to 4 days without the addition of exogenous colony stimulating factors (human placental-conditioned medium, HPCM). Survival... more
More than 20% of human granulocyte-macrophage and eosinophil colony-forming cells survived in agar culture for up to 4 days without the addition of exogenous colony stimulating factors (human placental-conditioned medium, HPCM). Survival was reduced slightly but not significantly, by the removal of adherent cell populations. Significant survival occurred even when only 100 cells enriched for colony-forming cells (CFCs) were cultured per dish. When individual colonies, initiated by stimulation with HPCM for 5 days, were transferred to dishes without HPCM, subsequent proliferation was significantly reduced compared with control cultures containing HPCM. Using the fluorescence-activated cell sorter and the fluoresceinated lectin from Lotus tetragonolobus, two populations of marrow cells were obtained, one enriched for day 7 and the other for day 14 colony-forming cells. Two colony-stimulating factors fractionated from HPLCM (CSF beta and CSF alpha) have been shown previously to stimulate the day 7 and day 14 colony-forming cell populations, respectively. Developing clones from cultures initiated with CSF beta died between the fifth and tenth day of culture after transfer to dishes with CSF alpha or CSF beta or to dishes with no stimulus. Cells in clusters initiated with CSF alpha proliferated significantly between the fifth and tenth day of culture when transferred to CSF alpha or CSF beta but not when transferred to dishes with not stimulus. These studies provide further evidence for the existence of two subtypes of human granulocyte-macrophage progenitor cells each under the primary control of a specific regulator and indicate that these two regulators can both act on some developing clones of cells.
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Xenograft intracerebral glioma models have been developed in normal mice by growing the rat C6 glioma in either adult or neonatal mouse brains. Using this tumor line it was possible to grow discrete intracerebral gliomas in either CBA or... more
Xenograft intracerebral glioma models have been developed in normal mice by growing the rat C6 glioma in either adult or neonatal mouse brains. Using this tumor line it was possible to grow discrete intracerebral gliomas in either CBA or AKR adult mice or neonatal mice. The size of the tumor mass and length of survival was directly related to the number of tumor cells injected and the time after implantation. To obtain localized intracranial tumor growth cells were suspended in a 1% agarose solution before implantation. Following injection of 10(6) cells into the frontal lobe of adult CBA or AKR mice, discrete tumor masses greater than 4 mm in diameter were obtained in 90% of animals at 14 days, and the largest tumors in adult mice occurred between 21 and 28 days after implantation. The tumor size following implantation of 10(6) cells was significantly greater than with 10(5) cells at 7 days (P less than 0.05) and at 14 and 21 days (P less than 0.01). Less than 60% of mice of BALB/c...
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ABSTRACT
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Stem cell factor (SCF), a ligand for c-kit, has a broad range of activities including effects on cells at or near the level of the multipotential stem cell as well as on committed cells. Preclinical studies show that SCF can protect... more
Stem cell factor (SCF), a ligand for c-kit, has a broad range of activities including effects on cells at or near the level of the multipotential stem cell as well as on committed cells. Preclinical studies show that SCF can protect against lethal irradiation, elicit multilineage responses in peripheral blood and bone marrow cellularity, and increase circulating peripheral blood progenitor cells (PBPC) in a dose-dependent manner. Recombinant human SCF has major clinical potential through its synergy with other factors, especially recombinant human granulocyte colony-stimulating factor, to enhance mobilization of PBPC.
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Photoirradiation treatment depends on exposing tumors to a photosensitizer and light to achieve selective tumor kill. We evaluated the kinetics of uptake of a photosensitizer, hematoporphyrin derivative (HpD), in an animal model of... more
Photoirradiation treatment depends on exposing tumors to a photosensitizer and light to achieve selective tumor kill. We evaluated the kinetics of uptake of a photosensitizer, hematoporphyrin derivative (HpD), in an animal model of cerebral glioma to ascertain the optimal time for photoirradiation therapy. Animal models of cerebral glioma were established by implanting cells from the rat C6 glioma cell line into rat brains or as xenografts in adult mouse brains. C6 cells (10(7] injected into the frontal lobe of adult Wistar rats produced intracranial tumors greater than 5 mm in diameter in 90% of the animals at 21 days. Tumors greater than 4 mm in diameter developed in adult mouse brains within 14 days after 10(6) cells were implanted into the frontal lobe. These two tumor models were used to investigate the localization of HpD. After HpD administration, its presence was detected in fresh, unfixed specimens by fluorescence emission after excitation with an ultraviolet lamp. Fluorescence was determined quantitatively by an image analysis method using an optical data digitometer. The fluorescence, which was highly localized selectively to the intracerebral tumor, was just detectable 5 minutes after an intravenous injection of HpD. Patchy, bright fluorescence was evident 4 hours after injection, and the tumor was uniformly fluorescent after 6 hours. A minimal dose of 0.5 mg of HpD per kg of body weight was necessary to produce detectable fluorescence, and the dose of HpD necessary to produce detectable fluorescence was 4 mg/kg of body weight. The intracarotid route of administration was unsatisfactory because seizures were induced, and intrathecal injection did not produce significant fluorescence in the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)
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The uptake of hematoporphyrin derivative (HpD) into human cerebral glioma was measured using a porphyrin extraction technique. Patients with cerebral glioma were injected with HpD at a dose of 5 mg/kg body weight 24 hours before surgery... more
The uptake of hematoporphyrin derivative (HpD) into human cerebral glioma was measured using a porphyrin extraction technique. Patients with cerebral glioma were injected with HpD at a dose of 5 mg/kg body weight 24 hours before surgery and photoradiation therapy (PRT). Biopsies of tumor, and where possible, adjacent brain and normal brain were taken for analysis of HpD uptake. HpD was selectively localized into all grades of glioma, and there was a direct correlation between the grade of glioma and HpD level in the tumor. The levels were highest in glioblastoma multiforme (mean uptake of 5.9 mg of HpD/g of tumor wet weight) and lower in the intermediate-grade anaplastic astrocytoma (mean uptake of 2.4 mg/g of tumor) and the low-grade astrocytoma (1.6 mg/g of tumor), Uptake into normal brain tissue taken from HpD-sensitized patients was 0.2 mg/g. HpD was also localized into the “brain adjacent to tumor” region. The selective uptake into the low-grade glioma suggests that PRT may be ...
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✓ Photoradiation therapy is a form of local treatment that depends on the selective retention of a photosensitizer, such as hematoporphyrin derivative (HpD), by the tumor followed by treatment with light of an appropriate wavelength to... more
✓ Photoradiation therapy is a form of local treatment that depends on the selective retention of a photosensitizer, such as hematoporphyrin derivative (HpD), by the tumor followed by treatment with light of an appropriate wavelength to activate the sensitizer in the tumor. The selective uptake of HpD by cerebral tumors has been demonstrated both in laboratory animal model studies and in clinical studies, and selective destruction of intracerebral tumors has been demonstrated in animal glioma models. The biological basis for photoradiation therapy and, in particular, the mechanisms for the selective uptake of the sensitizer into the tumor and the destruction of tumor with photoradiation therapy are discussed. Current evidence suggests that singlet oxygen is the major intermediary leading to cell damage, although other radicals such as hydrogen peroxide and hydroxyl radicals may be involved. Other studies suggest that the initial damage is to the blood vessels, and the tumor subsequen...
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✓ A Phase 1–2 study of high-dose photoradiation therapy was performed in 23 patients with cerebral tumors. Twenty-two patients had high-grade gliomas (13 glioblastomas, six recurrent glioblastomas, two anaplastic astrocytomas, and one... more
✓ A Phase 1–2 study of high-dose photoradiation therapy was performed in 23 patients with cerebral tumors. Twenty-two patients had high-grade gliomas (13 glioblastomas, six recurrent glioblastomas, two anaplastic astrocytomas, and one recurrent anaplastic astrocytoma) and one had a right frontal metastasis from a carcinoma of the lung. Hematoporphyrin derivative was administered to these patients in a dose of 5 mg/kg and, 24 hours later, they all underwent a craniotomy with radical excision of the tumor. The tumor bed was then irradiated with 630 nm of laser light from either an argon dye laser or a gold metal vapor laser for between 43 and 94 minutes, receiving total doses of 70 to 120 J/sq cm (six cases) or 120 to 230 J/sq cm (17 cases). The temperature of the tumor bed was kept below 37°C by irrigation. Fifteen patients who developed new tumors underwent postoperative radiotherapy (45 Gy in 20 divided doses). There was no evidence of increased cerebral edema and no other toxicity...
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SD/01, a sustained-duration molecule, has been developed by adding a poly [ethylene glycol] molecule to the filgrastim molecule. The pegylation does not change the properties of filgrastim, except that the plasma clearance is decreased... more
SD/01, a sustained-duration molecule, has been developed by adding a poly [ethylene glycol] molecule to the filgrastim molecule. The pegylation does not change the properties of filgrastim, except that the plasma clearance is decreased and plasma half-life is increased. Increasing the duration of the biological effects of filgrastim may offer certain groups of patients better benefits. Early clinical studies have been encouraging with no serious toxicities noted.
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only.
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The efficacy and toxicity of two regimens based on etoposide/carboplatin with or without cyclophosphamide/vincristine in the management of small cell lung cancer (SCLC) were assessed by the Australian Lung Cancer Study Group. Response... more
The efficacy and toxicity of two regimens based on etoposide/carboplatin with or without cyclophosphamide/vincristine in the management of small cell lung cancer (SCLC) were assessed by the Australian Lung Cancer Study Group. Response rates of 77% and 85% were noted for the two- and four-drug regimens, respectively, among patients with limited disease (LD). Response rates among patients with extensive disease (ED) were 58% and 79%, respectively. The profiles of nonhematologic toxicity were modest; myelosuppression was dose-limiting when colony-stimulating factors were not used. Twenty-six patients (14%) were older than 70 years of age. Although hematologic toxicity was more severe in the elderly group, there was no significant difference in nonhematologic toxicity, response rate, or overall survival between the geriatric and younger groups. When LD only was considered, 33% of those younger than 70 were alive at 2 years; no patients aged 70 years or older with LD were alive beyond 2 ...
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Research Interests: Biology, Biological Chemistry, Medicine, Cell Division, Biological Sciences, and 15 moreSoftware, Cell line, Humans, Biological, Monoclonal Antibodies, High Pressure Liquid Chromatography, CHEMICAL SCIENCES, Protein Conformation, Amino Acid Sequence, Recombinant Proteins, Epitopes, Enzyme Linked Immunosorbent Assay, Molecular Sequence Data, Neutralization tests, and Medical and Health Sciences
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Bacterially synthesized recombinant human granulocyte-macrophage colony- stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur... more
Bacterially synthesized recombinant human granulocyte-macrophage colony- stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur during short courses of administration. We have recognized a syndrome of hypoxia and hypotension that follows the first but not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study developed a reaction that occurred after the first dose of 24 of 78 cycles of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24), tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of 24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24), involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did not occur after any of more than 600 second and subsequent consecutive rhGM-CSF doses. Oxygen saturation decreased during ...
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As part of phase I/II clinical trials of granulocyte colony-stimulating factor (G-CSF), the pharmacokinetics was studied. To determine the optimal way of abrogating the neutropenia caused by melphalan, patients received G-CSF and... more
As part of phase I/II clinical trials of granulocyte colony-stimulating factor (G-CSF), the pharmacokinetics was studied. To determine the optimal way of abrogating the neutropenia caused by melphalan, patients received G-CSF and melphalan on several schedules. The half-life (t 1/2) of elimination of G-CSF was in the range 1.3 to 4.2 hours and was prolonged at higher doses, suggesting that one clearance mechanism becomes saturated at doses greater than 10 micrograms/kg, When a continuous subcutaneous (SC) infusion was administered for five days, a rapid reduction in serum G-CSF levels occurred during the last two days of the infusion, indicating that an additional clearance mechanism was induced. When a continuous infusion of G-CSF was administered after melphalan, serum G-CSF levels remained constant for a longer period of time but did decrease during the second phase of a biphasic neutrophil response. In another clinical trial, G-CSF was administered after high- dose chemotherapy ...
Research Interests: Clinical Trial, Medicine, Cancer treatment, Hematopoiesis, Cell Differentiation, and 14 moreHumans, Blood, Negative Feedback, Clinical Sciences, Neutrophils, Molecular cloning, Clinical Study, Side Effect, Growth Factor, Hematopoietic Stem Cell, Infusion Pumps, Cardiovascular medicine and haematology, Paediatrics and reproductive medicine, and leukocyte Count
A sensitive and reliable sandwich enzyme-linked immunosorbent assay (ELISA) has been developed for recombinant human granulocyte-macrophage colony-stimulating factor (hGM-CSF). The assay is quantitative between 100 pg/mL and 2.5 ng/mL for... more
A sensitive and reliable sandwich enzyme-linked immunosorbent assay (ELISA) has been developed for recombinant human granulocyte-macrophage colony-stimulating factor (hGM-CSF). The assay is quantitative between 100 pg/mL and 2.5 ng/mL for bacterially synthesized hGM-CSF in human serum and is more sensitive and specific than the semisolid agar bioassay. As part of a phase I study, the pharmacokinetics of intravenous (IV) bolus injection and subcutaneous (SC) administration of hGM-CSF were studied. Following a single IV dose, an initial high blood level of hGM-CSF occurred, followed by a rapid decrease occurring in two apparent phases with a half-life (t1/2)alpha of less than five minutes and a t1/2 beta of 150 minutes. After an SC injection, detectable serum levels occurred within 15 to 30 minutes, and serum levels were sustained for a variable time depending on the dose. At the highest SC dose (10 micrograms/kg), a serum level of greater than 1 ng/mL (65 pmol/L) was maintained for g...
Research Interests: Medicine, Humans, Mice, Female, Animals, and 14 moreBlood, Male, Monoclonal Antibodies, Bone marrow, Clinical Sciences, Aged, Middle Aged, Adult, Drug evaluation, Rabbits, Recombinant Proteins, Enzyme Linked Immunosorbent Assay, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
Human peripheral blood granulocytes, but not lymphocytes, erythrocytes, or monocytes, bound the fucose-binding lectin from Lotus tetragonolobus (FBP), and this binding was competitively inhibited by the sugar alpha- L-fucose. The... more
Human peripheral blood granulocytes, but not lymphocytes, erythrocytes, or monocytes, bound the fucose-binding lectin from Lotus tetragonolobus (FBP), and this binding was competitively inhibited by the sugar alpha- L-fucose. The fluorescence-activated cell sorter was used to study the appearance of this receptor on human marrow cells during granulocyte differentiation and to prepare fractions enriched for granulocyte- macrophage progenitor cells (granulocyte-macrophage colony-forming cells--GM-CFC). Cell binding of fluoresceinated FBP increased for bone marrow cells in the sequence--lymphocytes, blast cells, promyelocytes and myelocytes, monocytes, and polymorphonuclear cells. Selection of cells with appropriate low-angle or high-angle light scatter characteristics achieved a 10-fold or 2–3-fold enrichment of progenitor cells, respectively. By selecting cells with intermediate fluorescence intensity, a further 2–3-fold enrichment for GM-CFC was obtained. Cell sorting using the opti...
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An autoantibody that reacted with nuclei of polymorphonuclear neutrophils (PMN) was detected at titers of greater than 10 in sera of 25 of 50 patients with rheumatoid arthritis and 36 of 50 with autoimmune chronic active hepatitis but in... more
An autoantibody that reacted with nuclei of polymorphonuclear neutrophils (PMN) was detected at titers of greater than 10 in sera of 25 of 50 patients with rheumatoid arthritis and 36 of 50 with autoimmune chronic active hepatitis but in none of 160 controls comprising 24 patients with alcoholic cirrhosis, 36 with multiple myeloma, and 100 healthy subjects. Through the use of enriched populations of hemopoietic cells, this antibody was shown to be cell- specific, reacting only with the nucleus of the mature neutrophil. It was unreactive with nuclei of progenitor cells in the myeloid series and with nuclei of eosinophils, monocytes, lymphocytes, and thymocytes. It reacted with a determinant that appeared to be a differentiation antigen. This cell-specific autoantibody may prove to be of value in analytical studies of granulocyte maturation.
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Only 7 cases of primary lymphoma of the penis have been described previously. We report a case of diffuse large cell lymphoma of the glans penis. The clinical features, histology and management of these cases are reviewed. The previously... more
Only 7 cases of primary lymphoma of the penis have been described previously. We report a case of diffuse large cell lymphoma of the glans penis. The clinical features, histology and management of these cases are reviewed. The previously reported cases were treated with surgical resection or radiotherapy resulting in some degree of local morbidity. Our patient achieved complete remission after only 1 cycle of chemotherapy. The benefits of chemotherapy over surgery or radiotherapy for primary lymphoma of the penis are discussed.
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Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1,000 mg/m2/d for up to two weeks. Myelosuppression, especially thrombocytopenia, was the major systemic toxicity and... more
Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1,000 mg/m2/d for up to two weeks. Myelosuppression, especially thrombocytopenia, was the major systemic toxicity and limited the infusion period to nine to 14 days. However, bone marrow recovery occurred within seven to ten days, allowing for a second infusion in most patients. Local toxicity (within the radiation field) was minimal, with the exception of one of four patients, who underwent abdominal irradiation. Pharmacology studies revealed a steady-state arterial plasma level of 6 X 10(-7) mol/L and 1 X 10(-6) mol/L during infusion of 650 and 1,000 mg/m2/d, respectively. In vivo BUdR uptake into normal bone marrow was evaluated in two patients by comparison of preinfusion and postinfusion in vitro radiation survival curves of marrow CFUc with enhancement ratios (D0-pre/D0-post) of 1.8 (with 650 mg/m2/d) and 2.5 (with 1,000 mg/m2/d). In vivo BUdR incorporation into n...